Cyclopenteno[b]pyridine derivatives

ABSTRACT

The invention relates to novel cyclopenteno[b]pyridine derivatives which have a group X on the 7-position and related tricyclic compounds. X is CONHR 3 , or CO 2  R 5  wherein R 3  is hydrogen or lower alkyl and R 5  is hydrogen or a lower alkyl or lower aralkyl group which may be substituted by alkyl, alkoxy, halogen, nitro or trifluoromethyl; other substituents may be present. The compounds are intermediates for compounds wherein X is CSNHR 3  which are anti-ulcer agents.

The invention relates to novel cyclopenteno[b]pyridine derivatives andto related tricyclic compounds and is a continuation-in-part of ourco-pending application Ser. No. 600,257 filed July 30, 1975 which is acontinuation-in-part of our application Ser. No. 460,265, filed Apr. 11,1974, and now abandoned, which in turn is a continuation-in-part of ourSer. No. 403,289 filed Oct. 3, 1973, and now abandoned.

The invention provides a compound of formula I ##STR1## and acidaddition salts thereof with pharmaceutically acceptable acids, whereinR¹, R² and R⁶ are the same or different and are selected from hydrogen,trifluoromethyl, alkyl of 1 to 6 carbon atoms, phenylalkyl wherein thealkyl group has 1 to 6 carbon atoms, or phenyl groups, or R¹ and R²taken together represent an alkylene chain --CH₂ (CH₂)_(n) CH₂ --wherein n is an integer from 1 to 3, R⁷ represents hydrogen or 1 or 2groups selected from alkyl groups of 1 to 6 carbon atoms, which may besubstituted by alkoxy of 1 to 6 carbon atoms or trifluoromethyl;phenylalkyl wherein the alkyl group has 1 to 6 carbon atoms and phenylgroups, X is CONHR³ or CO₂ R⁵ wherein R³ is hydrogen or alkyl of 1 to 6carbon atoms and R⁵ is hydrogen, alkyl of 1 to 6 carbon atoms or phenylalkyl wherein the alkyl portion has 1 to 6 carbon atoms and any of thephenyl groups or the phenyl portion of any phenylalkyl groups R¹, R²,R⁵, R⁶ and R⁷ may be substituted by alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, halogen, nitro or trifluoromethyl and metalsalts of the compounds in which R⁵ is hydrogen, with the provisos that(1) when R¹ and R² or R² and R⁶ are both alkyl they are selected fromnormal and secondary alkyl groups and (2) when two alkyl groups R⁷ arepresent on the same carbon atom then they are both n-alkyl groups andwhen two R⁷ alkyl groups are present on adjacent carbon atoms they areselected from normal and secondary alkyl groups.

R⁷ may be in the same position as X.

When any of R¹, R², R³, R⁵, R⁶ or R⁷ is an alkyl radical this is a loweralkyl radical which may have a straight or branched chain, having from 1to 6 carbon atoms, e.g. methyl, ethyl, n-, and iso-propyl and n-, s- andt-butyl, R⁷ may be a gem-dimethyl group and when a single radical may beon the same carbon atom as the group X. The term alkyl radical is alsointended to embrace cyclic alkyl radicals e.g. cyclobutyl, cyclopentyland cyclohexyl. When any of R¹, R², R⁵, R⁶ or R⁷ is a phenyl alkylradical the alkyl portion may be as discussed above for an alkylradical.

Particularly preferred compounds are those in which one of R¹, R², R⁶and R⁷ is methyl and the others are hydrogen. Compounds wherein R³ isselected from hydrogen and methyl are also preferred.

Thus the present invention provides, in one preferred aspect, compoundsof formula II ##STR2## and acid addition salts thereof, wherein one ofR¹, R², R⁶ and R⁷ is selected from hydrogen and methyl and X is CONHR³or CO₂ R⁵, R³ and R⁵ being as defined in connection with formula I, andmetal e.g. alkali metal salts of those compounds wherein R⁵ is hydrogen.

The compounds of formula I can form acid addition salts with inorganicacids e.g. hydrochloric, hydrobromic, sulphuric or nitric acids, ororganic acids e.g. fumaric, maleic or tartaric acids. These acidaddition salts are included in the invention.

In the compounds of formula I the carbon atom to which X is attached isasymmetric. Consequently the compounds can exist in optically active dand l forms. These optically active forms and the racemates are includedin the invention. The optically active forms may be separated bystandard techniques either by formation of an acid salt with anoptically active acid or by use of an optically active base with acompound in which X is COOH.

Compounds of formula I are intermediates for corresponding compounds offormula I wherein X is CSNHR³, and these are anti-ulcer agents whichhave anti-ulcer activity as determined by the method of Brodie andHanson, J. Applied Physiology, 15, 291, 1960 or anti-secretory activityas determined by the test mentioned below. Compounds of formula I inwhich X is CONHR³ or CO₂ R⁵ or salts of those where X is CO₂ H aregenerally intermediates for compounds of formula I, in which X isCSNHR³. Compounds of formula I, wherein X is CSNHR³ often displayantisecretory activity in the test of H. Shay, D. Sun and H. Greenstein,Gastroenterology 1954, 26, 906-13.

The compounds of formula I are also intermediates for nitriles offormula I wherein X is CN and these are usually active in one of theabove tests. Compounds of formula I in which X is CN are alsointermediates for the thioamides of formula I in which X is CSNHR³.Compounds which exhibit activity in the above anti-ulcer oranti-secretory tests are regarded as anti-ulcer agents.

The compounds of formula I may be prepared by various methods all ofwhich are included in the invention.

A general method of preparing the compounds of formula I comprisestreating a corresponding compound in which X is hydrogen by knownmethods to introduce the desired group X.

A method for preparing compounds of formula I in which X is CO₂ R⁵comprises carboxylating a corresponding compound wherein X is hydrogen,to obtain a compound of formula I in which X is COOH or a metal saltthereof, and if desired esterifying the product with an hydroxylcompound R⁵ OH, wherein R⁵ is as defined above, except hydrogen. Thecarboxylation may be achieved by preparation of a metal salt of compoundof formula I wherein X is COOH, by treating a corresponding compound inwhich X is hydrogen, with a metal alkyl, followed by treatment of theproduct in situ with carbon dioxide, conveniently by bubbling CO₂ gasinto the reaction mixture. The compound of formula I in which X is CO₂ His obtained by treatment of the product, a metal salt of a compound offormula I in which X is COOH, with acid e.g. hydrochloric or hydrobromicacid. A convenient method is to treat a solution of the salt withgaseous hydrogen chloride. The metal alkyl may be one of a monovalentmetal e.g. MR¹⁰ wherein M is sodium, potassium or lithium and R¹⁰ isalkyl, aryl or aralkyl or one of a divalent metal M(R¹⁰)₂ wherein M iscalcium or magnesium. A convenient reagent MR¹⁰ is lithium phenyl orn-butyl lithium.

When a compound of formula I in which R¹ is methyl and R², R⁶ and R⁷ arehydrogen and X is hydrogen is carboxylated, the carboxylation may occureither on the methyl group R¹ or at the desired X position. If a mixtureof desired and undesired product is formed the desired product can beseparated during subsequent work-up.

The esterification of a compound of formula I in which X is CO₂ H may becarried out using an hydroxyl compound R⁵ OH, wherein R⁵ is as definedabove except hydrogen according to standard procedures, e.g. in thepresence of an acid catalyst e.g. some concentrated sulphuric acid orafter saturation with hydrogen chloride gas or a Lewis acid e.g. borontrifluoride if desired with heat or treatment of the silver salt, (X isCOOAg) with an iodide R⁵ I wherein R⁵ is as defined above, excepthydrogen.

The yield of ester can be improved by introducing a further quantity ofthe metal alkyl after the CO₂ treatment, followed by a further amount ofCO₂. It is believed that the further quantity of metal alkyl and CO₂gives the bis acid metal salt of formula IV ##STR3## wherein R¹, R², R⁶and R⁷ are as defined in connection with formula I and M is the metal ofthe metal alkyl e.g. sodium, potassium or lithium, and this saltspontaneously decarboxylates during the esterification.

A further method for preparing esters of formula I wherein X is CO₂ R⁵comprises treating a compound of formula I as defined above wherein X isa hydrogen atom with a metal alkyl (as defined above) and then treatingthe product with a haloformate of formula HalCOOR⁵ wherein Hal is ahalogen atom e.g. chlorine or bromine and R⁵ is as defined above. Theproduct is usually a mixture of the desired compound of formula Iwherein X is CO₂ R⁵ and the corresponding bis-ester of formula V##STR4## These bis-esters are useful for preparing the correspondingcompounds of formula I wherein X is CO₂ H. This mixture of mono and bisesters can be converted directly to the corresponding compound offormula I where X is CO₂ H, by saponification with an alkali or alkalineearth metal hydroxide to give a mixture of the metal salt of the monoacid of formula I wherein X is CO₂ H and the metal salt of the diacid offormula V wherein R⁵ is H. Treatment of this mixture with a mineral acide.g. hydrochloric acid gives the desired acid of formula I wherein X isCO₂ H since the diacid spontaneously decarboxylates to form the monoacid.

The product of the haloformate reaction may be treated with a furtherquantity of the metal alkyl followed by a further quantity of thehaloformate thereby producing more of the bis ester (V).

A further method for preparing compounds of formula I in which X is CO₂H comprises decarboxylation of a compound of formula V. ##STR5## whereinR¹, R² and R⁵ are as previously defined. The decarboxylation can becarried out by heating the dicarboxylic acid of formula V wherein R⁵ ishydrogen. Usually the dicarboxylic acid is prepared in situ byhydrolysis of the corresponding di-ester, wherein R⁵ is as defined aboveexcept hydrogen. The hydrolysis and decarboxylation may be carried outby heating with a dilute mineral acid e.g. HC1 or sulphuric acid or thediester may be saponified with alkali e.g. sodium or potassiumhydroxide. The resulting salt is then acidified and decarboxylated byheating

Compounds of formula I, in which X is CONHR³ may be prepared bytreatment of a corresponding compound of formula I wherein X is COC1 orCO₂ R⁵ and R⁵ is as defined above, except hydrogen, with ammonia to givea compound of formula I in which X is CONH₂, which may be subsequentlyalkylated to introduce the group R³ wherein R³ is as defined aboveexcept hydrogen. Conveniently a compound of formula I wherein X is CO₂R⁵ wherein R⁵ is lower alkyl, especially methyl or ethyl, is treatedwith ammonia. Alternatively substituted amides of formula I wherein X isCONHR³ and R³ is other than hydrogen may be prepared by treatment of thecarboxylic ester of formula I wherein X is CO₂ R⁵ and R⁵ is other thanhydrogen with an amine of formula R³ NH₂ wherein R³ is as definedpreviously except hydrogen. The substituted amides may conveniently beprepared from the acid chloride of formula I wherein X is COC1 bytreatment with a primary amine R³ NH₂.

An example of a primary amine which may be used in the above reactionsis methylamine.

The acid chlorides may be prepared by treatment of the correspondingacid of formula 1, wherein X is CO₂ H with thionyl chloride, phosphorusoxychloride or phosphorus pentachloride.

A further process for preparing compounds of formula I as defined abovewherein R¹ and R² are as defined above and X is CONHR³ wherein R³ ishydrogen or alkyl, comprises treating an ester compound of formula I,wherein X is CO₂ R⁵ and R⁵ is alkyl with an amide of formula R⁹ CONHR³or a salt thereof wherein R³ is hydrogen or alkyl and R⁹ is hydrogen orlower alkyl in the presence of an alkali-metal alkoxide.

Preferably a molar equivalent of alkali-metal alkoxide is used for eachmole of ester of formula I. The alkali-metal alkoxide may be one derivedfrom a lower alkanol having from 1 to 6 carbon atoms e.g. methanol orethanol. The alkali-metal is preferably sodium.

The ester of formula I is preferably a lower alkyl ester.

The amide R⁹ CONHR³ is preferably one in which R⁹ is hydrogen or methyl.R³ is also preferably hydrogen or methyl. Thus preferred amides areformamide, N-methyl-formamide, acetamide and N-methylacetamide. Salts,especially alkali-metal salts of these amides may be used as startingmaterials.

The reaction may be carried out by heating the reactants together. Theamides of formula I, wherein X is CONH₂ may also be prepared by partialhydrolysis of the corresponding nitriles of formula I, wherein X is CN.This hydrolysis may be accomplished in conventional manner e.g. byconcentrated (e.g. 96%) sulphuric acid.

Thioamides of formula I wherein X is CSNHR³ wherein R³ is as alreadydefined may be prepared by treatment of the corresponding compounds inwhich X is CONHR³ with P₂ S₅ e.g. by refluxing in pyridine. As mentionedbelow when the starting material is one in which X is CONH₂,decomposition to the nitrile may occur. We have found that thisdecmposition can be avoided by conducting the P₂ S₅ reaction in thepresence of H₂ S. Alternatively the thiomides may be prepared bytreatment of a nitrile of formula I, wherein X is CN with H₂ S to givethe unsubstituted thioamide wherein X is CSNH₂. Substituted thioamidesmay be obtained by conducting this reaction in the presence of a primaryamine R³ NH₂ wherein R³ is as defined above except hydrogen. The H₂ Sreaction can be carried out in a suitable solvent in the presence of acatalyst such as a tertiary amine e.g. a trialkylamine such astriethylamine.

Substituted thioamides may also be prepared by treatment of anunsubstituted thioamide of formula I, wherein X is CSNH₂ with an amineof formula R³ NH₂ wherein R³ is as previously defined is other thanhydrogen, in the presence of H₂ S. The amine may be a mono alkylaminee.g. methylamine.

The nitriles of formula I wherein X is CN, may be prepared bydehydration of the corresponding amides of formula I wherein X is CONH₂.Such dehydration can be carried out with P₂ O₅ as the dehydrating agent.Other dehydrating agents are phosphorus pentachloride or thionylchloride. It has also been found that this decomposition can be effectedwith P₂ S₅ and this is believed to be a novel reaction per se. Thedecomposition with P₂ S₅ has been observed as a side reaction during theconversion of the amides of formula I wherein X is CONH₂ to thecorresponding thioamides wherein X is CSNH₂ using P₂ S₅. The nitrile caneither be separated, e.g. by chromatography or the mixture treated withH₂ S for conversion of the nitrile to the corresponding thioamide. Thedehydration may also be effected by heating the amide inhexamethylphosphorictriamide as solvent. When using this solvent it hasbeen found that a compound of formula I in which X is CONMe₂ may beformed as a significant by-product. The latter is also believed to be anovel reaction per se.

A further method for preparing the thioamides of formula I, wherein X isCSNH₂ comprises reacting a nitrile of formula I wherein X is CN with athioamide of formula R⁸ CSNH₂ where R⁸ is an alkyl group, e.g. alower-alkyl group of 1- 6 carbon atoms, preferably a methyl group, in asuitable solvent such as dimethyl formamide saturated with hydrogenchloride.

The starting compounds of formula I wherein X is hydrogen, used in theabove mentioned carboxylation reaction may be prepared by cyclisation ofa compound of formula VI in the presence of hydroxylamine ##STR6##wherein R¹ and R² are as defined above but R¹ is preferably other thanhydrogen and R⁶ and R⁷ are as defined above. Starting compounds offormula I when X is hydrogen, R¹ is hydrogen and R⁷ is hydrogen, or ifnot hydrogen is not on the carbon adjacent to the R⁶ may be prepared byreduction of the corresponding 5-oxo compound (VII) using a reducingagent which does not affect the unsaturation of the fused pyridine ring.e.g. hydrazine i.e. Wolff-Kishner reduction. ##STR7##

The starting material of formula (VII) wherein R² and R⁶ are hydrogenmay be prepared by the following scheme: ##STR8##

The reaction can be carried out in a suitable solvent e.g.dimethylformamide at room temperature followed by distillation of theproducts.

Compounds of formula (I) wherein X is hydrogen, R¹ is hydrogen and R² isother than hydrogen may be prepared by known methods.

The compounds of formula VI (wherein R⁷ is hydrogen or is not on bothpositions adjacent the oxo group) may be prepared by one of thefollowing schemes: ##STR9## wherein R¹, R², R⁶ and R⁷ are as definedabove, R¹ being other than hydrogen. The reactants used are knowncompounds or may be prepared by methods known for analogous compounds.

Other compounds for preparing starting compounds of formula I wherein xis hydrogen are described in the literature e.g. Breitmaier & BayerTetrahedron Letters No. 38, 1970, 3291- 3295, which gives methods forpreparing compounds in which X is hydrogen and R¹ and R² are hydrogenand X is hydrogen and R² is alkyl.

The following Examples illustrate the invention and also the use of theproducts. In addition Examples directed to the preparation of analogousproducts are included. All temperatures are in °C.

EXAMPLE 1 (A) 2-Phenyl-5,6,7,8-tetrahydroquinoline

2-(3'-Phenyl-3'-oxopropyl) cyclohexanone was prepared according to themethod of W. Hahn and J. Epsztain (Roczniki Chem. 1963, 37, 403- 12): Amixture of β-dimethyl-aminopropiophenone (27 gm.) and cyclohexanone(37.5 g.) were heated at reflux for 5 hours under nitrogen and thesolvent removed in vacuo. The residual oil was distilled giving2-(3'-phenyl-3'-oxopropyl) cyclohexanone (14 g.) which was cyclised tothe title compound according to the method of Hahn and Epsztain bydissolving the diketone (12 g.) in ethanol (65 ml.), treating withhydroxylamine hydrochloride (9.g.) and heating under reflux for 1 hour.The cooled reaction mixture was poured onto water (300 ml.). extractedwith ether (2× 50 ml.) and the extracts discarded. The aqueous solutionwas made basic with K₂ CO₃ and extracted with ether (3× 50 ml.). thecombined ether extracts were dried and the solvent removed in vacuo. Theresidual oil was distilled to give the title compound as a colourlessoil (7 g.) b.p. 134°-8° C./15 mm. Found: C, 85.40; H, 7.5; N, 6.9%, C₁₅H₁₅ N requires: C, 86.00; H, 7.2; N, 6.7%

(B) Methyl2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

A solution of 2-phenyl-5,6,7,8-tetrahydroquinoline (20 g.) in ether (50ml.) was added dropwise over 30 mins. to a preformed ethereal solutionof phenyllithium (prepared from bromobenzene (40 g.) and lithium (2.78g.) in dry ether (160 ml.). The reaction mixture was stirred for 1 hourat room temperature and treated with dry CO₂ gas until the colour wasdischarged. The solvent was removed in vacuo and the residue dissolvedin ethanol saturated with dry HCl gas (250 ml.) and the solid filteredand recrystallised from water giving 2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylic acid hydrochloride (12 g.). This wasdissolved in methanol (200 ml.) and the solution treated with dry HClgas whilst heating at reflux for 4 hours. The solvent was removed invacuo and the residue dissolved in water (50 ml.), made basic with 2NNaOH and extracted into chloroform (3× 100 ml.). The combined extractswere dried, evaporated to dryness and the residual solid recrystallisedfrom petroleum ether giving the title compound as colourless needles (11g.) mp 75° C. Found: C, 76.8; H, 6.5; N, 5.14; C₁₇ H.sub. 17 NO₂requires: C, 76.4; H, 6.4; N, 5.2%.

EXAMPLE 2 2-Phenyl-5,6,7,8-Tetrahydroquinoline-8-carboxamide.

Methyl 2-phenyl-5,6,7,8-tetrahydroquinoline-8 -carboxylate (4 g.) wasdissolved in methanol previously saturated with ammonia (90 ml.) andheated in a bomb at 100° C. for 4 days. Removal of the solvent in vacuogave an oily solid which on recrystallisation from ethyl acetate gavethe title compound as colourless needles (1.5 g.) mp 145° C. Found: C,76.4; H, 6.5; N, 11.1% C₁₆ H₁₆ N₂ O requires: C, 76.2; H, 6.4; N, 11.1%.

EXAMPLE 3 2-Phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (8 g.) was dissolvedin pyridine (20 ml.), treated with P₂ S₅ (5.2 g.) and the mixture heatedat reflux temperature for 30 minutes. The solvent was removed in vacuoand the residual oil dissolved in dilute HCl, washed with ether (2× 50ml.) and the washings discarded. The aqueous solution was made basic,extracted into chloroform (3× 50 ml.) and the combined extracts driedand evaporated to dryness. The residual oil was chromatographed onsilica gel by elution with chloroform giving 8-cyano-2-pheny-5,6,7,8-tetrahydroquinoline (1.2 g.) as colourless needles fromether mpt. 100° C. Found: C, 82.0; H, 6.2; N, 11.7% C₁₆ H₁₄ N₂ requires:C, 82.0; H, 6.0; N, 11.9%. Further elution with chloroform gave thetitle compound (1.1 g.) as colourless needles from ether mpt. 154° C.Found: C, 71.8; H, 6.1; N, 10.2%, C₁₆ H₁₆ N₂ S requires: C, 71.6; H,6.0; N, 10.4%.

EXAMPLE 4 N,N-Dimethyl-2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide.

2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (6 g.) was dissolvedin hexamethylphosphorictriamide (24 ml.) and the solution heated at 220°C. for 2 hours. The cooled reaction mixture was poured onto water (50ml.), extracted with chloroform (3× 100 ml.) and the combined extractswashed with water (3× 100 ml.), dried and evaporated to dryness. Theresidual oil was chromatographed on silica gel by elution withchloroform giving 2-phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2.5 g.)recrystallised from ether as colourless needles mpt. 100° C. Furtherelution with chloroform gave N,N-dimethyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1.1 g.) which recrystallisedfrom ether as colourless needles mpt. 140° C. Found: C, 77.17; H, 7.22;N, 10.24%. C₁₈ H₂₀ N₂ O requires: C, 77.11; H, 7.19; N, 9.99%.

EXAMPLE 5 2-Phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g.) was dissolved inpyridine (5 ml.) and triethylamine (1.3 ml.) and the solution treatedwith H₂ S gas for 6 hours and the reaction mixture allowed to stand atroom temperature for 12 hours. Th solvent was removed and the residualoil dissolved in dilute HCl, extracted with ether (2× 50 ml.) and theextracts discarded. The aqueous solution was made basic and extractedinto chloroform (3× 50 ml.). The combined extracts were dried andevaporated in vacuo to give2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide which wasdissolved in ethanol (5 ml.), diluted with ether (25 ml.) and thesolution saturated with HCl gas. The solvent was removed in vacuo andthe residual solid recrystallised from methanol-ether givinghydrochloride of the title compound as colourless needles mpt. 211° C.Found: C, 63.41; H, 5.70; N, 8.94%. C₁₆ H₁₆ N₂ S. HCl requires: C,63.04; H, 5.62; N, 9.19 %.

EXAMPLE 6 (A) 5,6,7,8-Tetrahydroquinoline

5-Oxo-5H-6,7,8-trihydroquinoline was prepared according to the method ofF. Zymalkawski (Arch. Chem. 1961, 294, 759) by adding propiolaldehyde(16 g.) to a solution of 3-aminocyclohex-2-enone (31 g.) in DMF (150ml.) over 5 mins. When the exothermic reaction had ceased, the flask wasfitted for downward distillation and the reaction mixture heated at 100°C. under a vacuum of 15 mm. and the distillate collected and discarded.The temperature was raised to 160°-170° collecting the distillate whichwas dissolved in dilute HCl (75 ml.) and extracted with ether (2× 50ml.). The combined ethereal extracts were discarded. The aqueoussolution was made basic and extracted with ether (3× 150 ml.) and thecombined ethereal extracts dried and evaporated in vacuo. The residualoil was distilled giving 5- oxo-5H-6,7,8-trihydroquinoline (21 g.) b.p.133°-4° C./15 mm. which was dissolved in diethylene glycol (190 ml.) andtreated with hydrazine hydrate (14 g.) and sodium hydroxide (14 g.). Thereaction mixture was heated at reflux for 30 minutes and then for 31/2hours under a Dean and Stark water separator. The cooled reactionmixture was poured onto water (100 ml.), extracted with ether (3× 100ml.) and the combined extracts dried and evaporated in vacuo. Theresidual oil was distilled giving the title compound as a colourless oil(10 g.) b.p. 100°-5° C./15 mm.

(B) Methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate

A solution of5,6,7,8-tetrahydroquinoline (14 g.) in dry ether (100 ml.)was added dropwise over 1/2 hour to an ethereal solution of phenyllithium [prepared from bromobenzene (42 g.) and lithium (3.7 g.) in dryether (300 ml.)] and the reaction mixture stirred at room temperaturefor a further one hour. The cooled reaction mixture was saturated withdry CO₂ gas, evaporated in vacuo and the residue treated with methanolpreviously saturated with dry HCl (500 ml.) and the solution heated atreflux for 12 hours. The solvent was removed in vacuo and the residuedissolved in water (50 ml.), extracted with ether (3× 150 ml.) and theextracts discarded. The aqueous solution was made basic and extractedwith ether (3× 100 ml.). The combined ethereal extracts were dried,evaporated in vacuo and the residual oil distilled giving methyl5,6,7,8-tetrahydroquinoline-8-carboxylate as a colourless oil (13 g.)b.p. 92° C./0.05 mm. The hydrochloride was prepared by saturating anethereal solution with dry HCl gas and recrystallising the resultantsolid from methanol-ether to give the hydrochloride of the titlecompound as colourless needles mpt. 173° C. Found: C, 58.2; H, 6.3; N,6.3%. C₁₁ H₁₃ NO₂.HCl requires C, 58.0; H, 6.2; N, 6.2%.

EXAMPLE 7 5,6,7,8-Tetrahydroquinoline-8-carboxamide

Methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate (9 g.) was dissolved inmethanol previously saturated with ammonia (270 ml.) and heated in abomb at 100° C. for 5 days. The solvent was removed and the residual oiltriturated with hot petroleum ether (40°-60°). The resultant solid wasfiltered and then recrystallised from ethyl acetate giving the titlecompound as colourless needles mpt. 132° C. (5 g.). Found: C, 67.7; H,7.1; N, 16.0% C₁₀ H₁₂ N₂ O requires: C, 68.1; H, 6.9; N, 15.9%.

EXAMPLE 8 5,6,7,8-Tetrahydroquinoline-8-thiocarboxamide

A solution of 5,6,7,8-tetrahydroquinoline-8 -carboxamide (1.2 g.) inpyridine (15 ml.) was treated with P₂ S₅ (0.8 g.) and the mixture heatedat reflux for 30 mins. The solvent was removed in vacuo and the residualoil treated with 2N NaOH (5 ml.) and saturated with solid K₂ CO₃ andextracted into chloroform (3× 50 ml.). The combined extracts were driedand the solvent removed in vacuo. The residual oil was dissolved inpyridine (4 ml.) and triethylamine (1 ml.) and the solution saturatedwith H₂ S (6 hours) and allowed to stand overnight. Removal of thesolvent gave a solid (850 mgs.) which was recrystallised from methanolgiving the title compound as the quarter hydrate, colourless needlesm.p. 160° C. Found: C, 59.8; H, 6.2; N, 14.0%. C₁₀ H₁₂ N₂ S.1/4 H₂ Orequires: C, 59.6; H, 6.4; N, 13.9%.

    ______________________________________                                          The UV, IR and NMR Spectra of the title compound were                       determined:                                                                   1.  UV Spectrum in 95% EtOH (1.07 mg. in 100 ml.)                                 Max 272 nm, ε13,300                                               2.  IR Spectrum                                                                    ##STR10##                                                                1660 cm.sup..sup.-1                                                                        --NH.sub.2 deformation or/and C=CN                                            stretch                                                          1575 cm.sup..sup.-1                                                                        C=C stretch                                                      1500-900 cm.sup..sup.-1                                                                    'fingerprint region'; numerous bands                                          caused by complex and coupled                                                 vibrations.                                                                   Two bands are particularly prominent                                          1280 cm.sup..sup.-1 and 1020 cm.sup..sup.-1                       ##STR11##    --CH deformation, characteristic of  2,3-disubstituted                       pyridine.                                                        3.  NMR Spectrum - in d.sub.6 DMSO (100 MH.sub.2)                             δ1.5-2.3                                                                            broad multiplet                                                                            4 protons CH.sub.2 -6                                                                   and 7                                      δ2.7  multiplet    2 protons CH.sub.2 -5                                δ4.15 triplet (J=7Hz)                                                                            1 proton  CH-8                                       δ7.08 quartet      1 proton  H-3                                        δ7.44 quartet      1 proton  H-4                                        δ8.29 quartet      1 proton  H-2                                        δ9.25 and                                                                           broad doublet                                                                              2 protons NH.sub.2                                     9.45                                                                        Coupling constants = J.sub.23 = 5Hz, J.sub.24 = 1.5 Hz, J.sub.34 = 8          ______________________________________                                        Hz                                                                        

It is indicated in the index to Chemical Abstracts that5,6,7,8-tetrahydroquinoline-8-thiocarboxamide is disclosed in Z.Naturforch. 6b. 147-155 (1951), however, the actual abstract does notdisclose the compound and examination of the paper reveals that theindex is in error since the compound actually disclosed in 8-quinolinethiocarboxamide, the benzene ring of which has been shown without theunsaturation being marked in accordance with a custom then in use, seeOrganic Chemistry, Paul Karrer, 4the English Edition, Elsevier, 1950 eg.at page 813.

EXAMPLE 9 (A) 2-t-Butyl-5,6,7,8-tetrahydroquinoline

5-Dimethylamino-2,2-dimethylpentan-3-one hydrochloride (100 g.),prepared from pinacolone according to the method of Casey & Ison(Tetrahedron, 1969, 25, 641-6) was dissolved in water (50 ml.) and thepH adjusted to 12.0 with 10N NaOH and extracted with ether (3× 50 ml.).The combined ethereal extracts were dried (MgSO₄), evaporated in vacuoand the residual oil dissolved in cyclohexanone (300 ml.). The mixturewas heated at reflux temperature for 8 hours and then cooled. Thereaction mixture was then distilled at 15 mm. to remove excesscyclohexanone and then at 1 mm. to give 2(3'-t-butyl-3'-oxopropyl)cyclohexanone (82 g.) which was dissolved in ethanol(275 ml.) and treated with hydroxylamine hydrochloride (70 g.). Themixture was heated at reflux temperature for 2 hours as described in thegeneral method of W. Hahn and J. Epsztain (Roczniki Chem. 1963, 37,403-12). The solvent was removed in vacuo and the residual oil dissolvedin ether (100 ml.). The ethereal solution was washed with dilute HCl (3×20 ml.) and discarded. The aqueous solution was made basic with 2N NaOHand extracted with ether (3× 50 ml.) and the combined extracts dried andevaporated in vacuo. The residual oil was distilled giving the titlecompound as a colourless oil b.p. 80°-6° C./1 mm. (yield 47 g., 64%).

(B) 2-t-Butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

Methyl 2-t-butyl-5,6,7,8-tetrahydroquinoline-8 -carboxylate was preparedfrom 2-t-butyl-5,6,7,8-tetrahydroquinoline (18.9 g., 0.1 m). and phenyllithium (0.1 m.) by the general method described in Example 1B and wasisolated as a pale yellow oil (9 g.) b.p. 106° C./0.4 mm.

The title compound was prepared from methyl 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (8 g.) by the generalmethod described in Example 2 and was isolated as colourless needles (3g.) after recrystallisation from n-hexane m.p. 131° C. Found: C, 72.06;H, 8.71; N, 11.62%. C₁₄ H₂₀ N₂ O requires: C, 72.38; H, 8.68; N, 12.06%.

EXAMPLE 10 2-t-Butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

The title compound was prepared from2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (4 g.) and P₂ S₅ (3g.) as described in Example 8 and was isolated as creamy needles afterrecrystallisation from n-hexane m.p. 126° C. (650 mgs.) Found: C, 68.18,H, 8.25; N, 11.14%. C₁₄ H₂₀ N₂ S requires C, 67.70; H, 8.12; N, 11.23%.

EXAMPLE 11 5,6,7,8-Tetrahydroquinoline

3-Methoxyacrolein was prepared from 1,1,3,3-tetramethoxypropane (Helv.Chim. Acta 1959, 42, 851) and converted to 3-aminoacrolein according tothe method of Breitmaier and Gassenmann (Chem. Ber. 1971, 104, 665-7).

5,6,7,8Tetrahydroquinoline was prepared from 3 -aminoacrolein asdescribed by Breitmaier and Bayer (Tet. Letts 1970, 38, 3291). A mixtureof 3-aminoacrolein (7.3 gm, 0.1 m) and cyclohexanone (12 gm., 0.12m) wastreated with triethylamine (5 ml.) and piperidinium acetate (0.1 gr) andthe mixture heated in an oil bath at 120° for 24 hours. The cooledreaction mixture was dissolved in ether (100 ml.), washed with water and2N HCl (2× 20 ml.) and the acid washings combined, made basic withsodium carbonate and extracted with ether. The combined extracts weredried, evaporated and the residue distilled to give the title compoundas a pale yellow oil (4.5 gm, 35%) b.p. 100°/15 mm.

EXAMPLE 12 2-Methyl-5,6,7,8tetrahydroquinoline

4-Diethylaminopropan-2-one prepared from acetone and diethylamine(J.C.S. 1937, 53) was reacted with cyclohexanone by the general methoddescribed in C.A. 72, 132478h to give 2-(3'-methyl-3'-oxopropyl)cyclohexanone as a colourless oil b.p. 150°/20 mm.

The title compound was prepared from 2-(3'-methyl-3'-oxopropyl)cyclohexanone according to the general method described inExamples 1 and 9A and isolated as a colourless oil b.p. 116°-20°/18 mm.(60% yield).

EXAMPLE 13 2-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

Reaction of 2-methyl-5,6,7,8-tetrahydroquinoline with phenyl lithium andcarbon dioxide followed by esterification according to the generalmethod described in Examples 1B and 6B gave an inseparable mixture ofmethyl 2-methyl- 5,6,7,8-tetrahydroquinoline-8-carboxylate and methyl5,6,7,8-tetrahydroquinoline-2-acetate which was coverted withoutpurification to a mixture of 2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide and 5,6,7,8-tetrahydroquinoline-2-acetamide by reaction with ammonia using the method described inExample 2. Fractional recrystallisation from diisopropyl ether gave thetitle compound as colourless needles m.p. 114° (overall yield 30%)(Found: C, 69.31, H, 7.45, N, 14.7, C₁₁ H₁₄ N₂ O requires: C, 69.45, H,7.42; N, 14.72%).

EXAMPLE 14 2-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

2-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide was treated with P₂S₅ to give 2-methyl-8-cyano-5,6,7,8 -tetrahydroquinoline which wastreated with H₂ S (both reactions being carried out by the methoddescribed in Example 8 to give the title compound as colourless needlesfrom ethyl acetate (28%) m.p. 98° (Found: C, 64.32; H, 6.93; N, 13.52%,C₁₁ H₁₄ N₂ S requires: C, 64.04; H, 6.84; N, 13.58%).

EXAMPLE 15 3-Methyl-5,6,7,8-tetrahydroquinoline

The title compound was prepared from commercially available3-amino-2-methylacrolein and cyclohexanone according to the method ofBreitmaier and Bayer (Tet. Letts, 1970, 38, 3291- 4) and isolated as apale yellow oil b.p. 120°/15 mm. (30% yield).

EXAMPLE 16 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

The title compound was prepared from 3-methyl-5,6,7,8-tetrahydroquinoline according to the general method described inExample 1B and isolated as a pale yellow oil b.p. 120°/0.25 mm. (80%yield). The hydrochloride was prepared in the usual way (cf Example 6B)and isolated as colourless needles from ethanol/ether m.p. 146° (Found:C, 59.9; H, 6.7; N, 6.0. C₁₂ H₁₅ NO₂ HCl requires: C, 59.60; H, 6.7; N,5.8%).

EXAMPLE 17 3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

The title compound was prepared from methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate by the method described inExample 2 and was isolated as colourless needles from hexane m.p. 118°(50% yield) (Found: 69.60; H, 7.5; N, 14.8; C₁₁ H₁₄ N₂ O requires: C,69.5; H, 7.4; N, 14.7%).

EXAMPLE 18 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide was treated with P₂S₅ to give 3-methyl-8-cyano-5,6,7,8 -tetrahydroquinoline which wastreated with H₂ S as described in Example 8 giving the title compound ascolourless needles from benzene m.p. 151° (50% yield) (Found: C, 63.71;H, 6.85; N, 13.38% C₁₁ H₁₄ N₂ S requires: C, 64.04; H, 6.84; N, 13.58%).

The hydrochloride was prepared by dissolving the title compound in theminimum amount of isopropanol and then adding a solution of ethersaturated with dry HCl gas. The hydrochloride precipitated as colourlessneedles m.p. 219° (Found: C, 54.33; H, 6.23; N, 11.42% C₁₁ H₁₄ N₂ SHClrequires: C, 54.42; H, 6.23; N, 11.54%).

EXAMPLE 19 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

N-Butyl bromide (285 ml.) in dry ether (500 ml.) was added to cleanlithium wire (42 g., 6 m) in dry ether (1 l.) under nitrogen at such arate to maintain an internal temperature of -15° C. Upon completion ofthe addition the reaction mixture was stirred until the temperature roseto 10° C. (approx. 2 hours). The concentration of butyl lithium wascalculated by standardising against N/10 HCl and the quantity of 3-methyl-5,6,7,8-tetrahydroquinoline required in the next stage adjustedto have a 0.2 m excess of butyl lithium.

A stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (147 g., 1 m)in dry ether (700 ml.) was treated with a freshly prepared solution ofbutyl lithium (860 ml. of a 1.4 M solution i.e. 1.2 m) under nitrogen.The reaction mixture was stirred for an additional 15 min. and a slowstream of dry CO₂ gas bubbled into the reaction mixture untilcolourless. The reaction mixture was diluted with water (1.2 l),filtered and the aqueous phase separated and extracted with ether (3×500 ml.). The combined ethereal extracts were processed to giverecovered 3 -methyl-5,6,7,8-tetrahydroquinoline (40 g.) b.p. 116°-20°/15mm.

The aqueous layer was evaporated to dyrness and the residual solidtreated with a solution of methanol previously saturated with dry HClgas (1.5 l) and allowed to stand at room temperature for 12 hours. Thevolatiles were removed in vacuo. The residual oil was redissolved inwater (1 l.), extracted with ether (3× 250 ml.) and the extractsdiscarded. The aqueous solution was adjusted to pH 9.0 with Na₂ CO₃ andextracted with ether (4× 250 ml.). The combined extracts were dried andthe solvent removed in vacuo to give the title compound as a pale yellowoil (85 g. 42%) GLC (10% SE30, T= 200°) R₁ = 3.25 min, 93% pure.

EXAMPLE 20 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (5 g., 0.034 m) indry ether (50 ml.) was treated portion- wise with a solution of butyllithium in hexane (0.04 m) under nitrogen and the mixture allowed tostand at room temperature for 30 minutes. A slow stream of CO₂ gas wasbubbled in until the reaction mixture was colourless. A further 0.02 m.of butyl lithium in hexane solution was added. The mixture was allowedto stand for 30 minutes and then treated with dry CO₂ gas as above. Thereaction mixture was diluted with water (20 ml.), the aqueous layerextracted with ether (3× 50 ml.) and the combined extracts retained forrecovery of unreacted 3-methyl-5,6,7,8-tetrahydroquinoline. The aqueousphase was evaporated to dryness in vacuo. The resultant solid wastreated with methanol previously saturated with dry HCl gas (50 ml.) andallowed to stand at room temperature for 3 hours. The solvent wasremoved and the residual oil dissolved in water (20 ml.) and extractedwith ether (3× 25 ml.) and the extracts discarded. The aqueous phase wasadjusted to pH 9.0 with Na₂ CO₃ and extracted into ether (3× 50 ml.).The combined extracts were dried and evaporated in vacuo to give thetitle compound as a colourless oil (4.3 g., 60%) GLC (10% SE30, T=200°). R₁ = 3.25 min. 98% pure.

EXAMPLE 21 3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

A mixture of methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate(25 g., 0.13 m), formamide (11.6, 0.26 m) and sodium methoxide (from2.99 g., 0.13 m sodium) was heated with stirring in an oil bath at 120°from 1 hour. The reaction mixture was further heated at 100° for 3 hoursunder reduced pressure (15 mm Hg). The cooled reaction mixture wasdiluted with 2N HCl to give an acidic solution which was extracted withethyl acetate (2× 50 ml.) and the combined extracts discarded. Theaqueous solution was adjusted to pH 9.0 with solid Na₂ CO₃, saturatedwith NaCl and extracted with chloroform (3× 100 ml.). The combinedextracts were dried and evaporated to give a pale yellow oil whichsolidified on trituration with n-hexane. Recrystallisation from ethylacetate gave the title compound as colourless cubes (18.6 g., 88%) m.p.110°. Found: C, 69.6; H, 7.4; N, 14.4%. C₁₁ H₁₄ N₂ O requires: C, 69.5;H, 7.4; N, 14.7%.

EXAMPLE 22 3-Methyl-5,6,7,8-Tetrahydroquinoline-8-carboxamide

A mixture of methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate(25 g. 0.13 m), formamide (11.6 g., 0.26 m) and sodium methoxide (from2.99 g., 0.13 m sodium) was heated on a steam bath for 1 hour whilebubbling nitrogen through the mixture, to blow off the methyl formateproduced in the reaction. The cooled reaction mixture was diluted with2N HCl and worked up as described in Example 21 to give the titlecompound in 90% yield.

EXAMPLE 23 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9g. 0.14 m) in dry pyridine (300 ml.), saturated with H₂ S gas, wastreated with P₂ S₅ (26 g., 0.14 m) and heated at reflux for 45 min.whilst maintaining a slow stream of H₂ S gas. The reaction mixture wasevaporated to dryness in vacuo and cooled to 0° C., made alkaline with10% sodium hydroxide and the solution extracted with chloroform (3× 100ml.). The combined extracts were washed with brine, dried and evaporatedin vacuo. The residual oil was triturated with benzene and the solidfiltered and recrystallised from benzene to give the title compound aspale yellow needles m.p. 149° (21.8 g., 87%). The hydrochloride wasprepared as already described in Example 18 and isolated as colourlessneedles m.p. 219° C.

EXAMPLE 24 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

Charge a 3-necked flask with 3-methyl-5,6,7,8-tetrahydroquinoline (45 g.0.29 moles) and ether (400 ml.). Stir. Add phenyl lithium solution (330ml. of a 1 molar solution 0.3 moles in ether) at a rate to give gentlereflux. Maintain reflux for 2 hours. Cool in an ice-bath and bubble CO₂through solution till no further change. Add water (700 ml.) to dissolvesolid. Separate and wash aqueous layer with ether (3 times). Evaporateaqueous layer to dryness in vacuo. To the residue add a saturatedsolution (1 liter) of methanolic HCl and stand overnight at roomtemperature. Evaporate to dryness in vacuo and dissolve residue inwater. Wash water with ether (3 times). Basify aqueous solution withsolid sodium carbonate and extract with ether (a heavy white solid alsoprecipitates, but this does not interfere with the extraction). Washether layer with water, then brine. Dry and evaporate. Yield 25 g.(44%). GLC= 88% pure.

EXAMPLE 25 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

A solution of 15% n-butyl lithium in hexane (51 ml. ca. 0.12 m) wasadded portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline(14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand atroom temperature for 1 hour then added dropwise to a cooled, stirredsolution of methyl chloroformate (9.45 g., 0.1 m) in ether (100 ml.).The mixture was stirred at 50° C. for 1 hour. The reaction mixture wasdiluted with water (20 ml.) and then treated with 2N HCl until acidic.The ethereal solution was separated and washed with 2N HCl (2× 25 ml.).The combined aqueous washings were extracted with ether and the etherealextracts discarded. The aqueous solution was adjusted to pH 9.0 with Na₂CO₃ and extracted with chloroform (3× 50 ml.) and the combined extractsdried and evaporated to give a pale yellow oil (16 g) which on GLCexamination (3% SE30) showed a mixture of unreacted tetrahydroquinoline(45%), the title compound (23%) and the 8,8-dicarboxylic ester (20%).The mixture was treated with 10% sodium hydroxide (75 ml.). and heatedat reflux with stirring for 4 hours, cooled and extracted with ether (3×50 ml.). The combined ethereal extracts were dried, evaporated anddistilled to give unreacted 3-methyl-5,6,7,8-tetrahydroquinoline (7 g.)b.p. 116°/18 mm Hg. The basic solution was adjusted to pH 8.5-9.0 withconcentrated HCl and evaporated to dryness and the residue treated withmethanol previously saturated with dry HCl (50 ml.) and allowed to standat room temperature for 5 hours. The solvent was removed and the residuedissolved in water (20 ml.) and extracted with ether (2× 50 ml.). Theaqueous solution was adjusted to pH 9.0 with Na₂ CO₃ and extracted withchloroform (3× 25 ml.) and the combined extracts dried and evaporated togive the title compound (3 gm.).

EXAMPLE 26 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamidehydrochloride Crystal Form A

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1 g.) preparedas described in Example 18 was dissolved in boiling isopropyl alcohol(25 ml.), filtered and allowed to cool to 40° C. An excess of anethereal solution of hydrogen chloride was added followed by sufficientether to cause turbidity. On cooling the title compound was isolated asfine colourless needles (0.95 g.) mpt 244° C. Found: C, 54.3; H, 6.2; N,11.4%. C₁₁ H₁₄ N₂ S.HCl requires C, 54.4; H, 6.2; H, 11.5;L %. I.R.ν.sub. max^(Nujol) Mull 3300 (shoulder), 3230 (broad), 3060 (broad),2540 (broad), 1650 (strong), 1605, 1555 cm.sup.⁻¹. This I.R. Spectrumwas identical with that exhibited by the product of Example 18.

Crystal Form B

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1 g.) preparedas described in Example 18 was dissolved in boiling isopropyl alcohol(15 ml.) and a slight excess of an ethereal solution of hydrogenchloride added without cooling. The title compound was obtained as finecolourless needles (950 mg) m.p. 244° C. Found: C, 54.58; H, 6.29; N,11.34%. C₁₁ H₁₄ N₂ S. HCl requires C, 54.42; H, 6.23; N, 11.54%. I.R.ν.sub. max^(Nujol) mull 3260 (broad), 3220 (broad), 3050, 2630 (broad),1655-1630 (3 sharp bands), 1555cm⁻¹.

Crystal Form B-- Alternative Method

3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.5 g.) wasdissolved in methanol (1 ml.) and treated with methanol saturated withhydrogen chloride (1 ml.) and the solution heated to boiling. Ethylacetate was added, whilst the methanol evaporated, until turbid. Oncooling the title compound was isolated as fine colourless needles (0.4g.) m.p. 244°. Found: C, 54.11; H, 6.18; N, 11.31%. C₁₁ H₁₄ N₂ S.HClrequires: C, 54.42; H, 6.23; N, 11.54%. Crystal Form A could not beconverted into crystal form B by crystallising from isopropyl alcoholether or methanol/ethyl acetate.

Form A on standing for 2-3 days reverted to Form B. Form A could also beconverted to Form B by heating at 40° C. under vacuum for 6 hours.

EXAMPLE 27 3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide CrystalForm A

3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1 g.) prepared asdescribed in Example 17 was dissolved in boiling di-isopropyl ether (80ml.), filtered and allowed to cool. The title compound was isolated asfine colourless cubes (0.85 g.), m.p. 118° C. Found: C, 69.6; H, 7.5; N,14.8%. C₁₁ H₁₄ N₂ O requires C, 69.5; H, 7.4; H, 14.7%. I.R. ν.sub.max^(nujol) 3395, 3195, 1650 (strong), 1620, 1605 (shoulder), 1595,1560, 1235, 875 (strong), 620 (strong) cm¹¹⁶ 1. The I.R. Spectrum wasidentical with that of the product of Example 17.

Crystal Form B

3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1 g.) prepared asdescribed in Example 17 was dissolved in boiling ethyl acetate (2 ml.),filtered and allowed to cool. The title compound was isolated ascolourless rhombic crystals (0.80 g.) m.p. 113°. Found: C, 68.81; H,7.40; N, 14.45%. C₁₁ H₁₄ N₂ O requires C, 69.50; H, 7.40; N, 14.70%.I.R. ν.sub. max^(nujol) 3395, 3280, 3185, 1680 (strong) 1605, 1595,1560, 900 (strong), 575 (strong) cm¹¹⁶ 1.

The crystal forms A and B can be interconverted by crystallisation fromthe appropriate solvents. Thus crystallisation of form A from ethylacetate will give form B and crystallisation of form B from di-isopropylether will give form A.

EXAMPLE 28 3-Methyl-5,6,7,8-tetrahydroquinoline-8-(N-methyl)thiocarboxamide

Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (5 gm.) wasdissolved in 33% methylamine in ethanol (50 ml.) and the solution heatedat 150° for 24 hours in a stainless steel bomb. The solvent was removedin vacuo and the residual oil crystallised on standing.Recrystallisation from 2-propanol/n-hexane gave3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-methyl)carboxamide ascolourless needles (4 gm., 85%). A sample was characterised as thehydrochloride which was obtained by treating a solution of the base inethanol with ethereal HCl and isolated as colourless needles m.p. 185°.

(Found: C, 59.81; H, 7.11; N, 11.34%. C₁₂ H₁₆ N₂ O.HCl requires C,59.87; H, 7.12; N, 11.64.

A solution of3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-methyl)carboxamide (1.2 g.) inpyridine (9 ml.) was treated with phosphorus pentasulphide (1.2 g.) andthe mixture heated at reflux for 3 hours. The solvent was removed invacuo and the residue treated with a 10% aqueous solution of sodiumhydroxide until alkaline. The solution was extracted with chloroform (3×50 ml.) and the combined extracts washed with water (2× 20 ml.) brine,dried and evaporated. The residual oily solid was recrystallised frombenzene to give the title compound as colourless needles (0.9 g., 65%)m.p. 159° (Found: C, 65.12; H, 7.26; N, 12.56% C₁₂ H₁₆ N₂ S requires: C,65.41; H, 7.32; N, 12. 72% ).

EXAMPLE 293-Methyl-5,6,7,8-tetrahydroquinoline-8-(N-n-butyl)thiocarboxamide

Following the general procedure of Example 28, methyl3-5,6,7,8-tetrahydroquinoline-8-carboxylate is treated with n-butylamineto give 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-n-butyl) carboxamidewhich is treated with phosphorus pentasulphide in pyridine to give thetitle compound which is obtained as a yellow oil. The oil is dissolvedin an excess of ether saturated with HCL gas. The resulting solid isrecrystallised from isopropanol to give the hydrochloride of the titlecompound as colourless needles m.p. 195° C.(dec.)

EXAMPLE 30 Sym. Octahydroacridine-4-thiocarboxamide

Sym. octahydroacridine was prepared by converting cyclohexanone todi-(2-oxo-cyclohex-1-yl)-methane and further reacting with hydroxylamineaccording to the method of Gill et al (JACS 1952, 74, 4923) and wasisolated as a colourless oil b.p. 110°-15°/0.5 mm. in 40% overall yield.

A solution of sym. octahydroacridine (5 gm. 0.026 m.) in dry ether (50ml.) was treated dropwise with a 15% solution of butyl lithium in hexane(11 ml. 0.026 m) and the mixture stirred at room temperature for 15 min.under an atmosphere of nitrogen. The nitrogen was replaced by CO₂ gaswhich was bubbled through the reaction mixture until colourless. Thereaction mixture was diluted with water (50 ml.) and the organic layerseparated and the aqueous phase extracted with ether (2× 50 ml.). Thecombined extracts were retained for recovery of sym. octahydroacridine.The aqueous phase was evaporated to dryness, the residue treated withmethanol prevously saturated with dry HCl (50 ml.) and the solutionallowed to stand at room temperature for 3 hours. The solvent wasremoved in vacuo the residue diluted with water (20 ml.) and extractedwith ether. The aqueous phase was adjusted to pH 10. with solid Na₂ CO₃and extracted with ether (3× 20 ml.). The combined extracts were washedwith brine, dried and evaporated to give methyl sym.octahydroacridine-4-carboxylate. (1 gm. 15%).

A solution of methyl sym octahydroacridine-4-carboxylate (5 gm) inmethanol previously saturated with ammonia (80 ml.) was heated at 140°for 3 days in a stainless steel bomb. The solvent was removed and theresidual solid recrystallised from di-isopropyl ether to give sym.octahydroacridine-4-carboxamide as colourless needles (2.6 g, 57%) m.p.159° (Found: C, 72.98; H, 8.04; N, 12.01%. C₁₄ H₁₈ N₂ O requires: C,73.01; H, 7.88; N, 12.17%).

A solution of sym. octahydroacridine-4-carboxamide (1.8 gm.) in pyridine(17 ml.) was treated with hydrogen sulphide for 5 mins. The reactionmixture was treated with phosphorus pentasulphide (1.4 g.) and heated atreflux for 45 mins maintaining a slow stream of hydrogen sulphidethroughout. The cooled reaction mixture was evaporated and the residuetreated with 10% sodium hydroxide until alkaline. The aqueous solutionwas extracted with chloroform (3× 50 ml.) and the combined extractswashed with brine, dried and evaporated and the residual solidrecrystallised from di-isopropyl ether giving the title compound as apale yellow powder (0.3 g. 16% ) m.p. 104°-6° (solidifies and remelts at148°). (Found: C, 68.69; H, 7.54; N, 10.98%. C₁₄ H₁₈ N₂ S requires: C,68.26; H, 7.36; N, 11.37%).

EXAMPLE 31 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamideoxalate

To a solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide(1 g.) in hot ethanol (10 ml.) was added a solution of oxalic aciddihydrate (650 mg.) in hot ethanol (6.5 ml.). The solution was filteredand allowed to cool when the oxalate crystallised. The oxalate wasremoved by filtration, washed with ether and dried. Yield 1 g. 186°-8°C. Found: C, 52.71%; H, 5.63%; N, 9.19%. Calc. for C₁₃ H₁₆ N₂ O₄ S: C,52.70%, H, 5.44%; N, 9.46%.

EXAMPLE 32 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamidetartrate

To a solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide(13 g.) in hot isopropyl alcohol (130ml.) was added a solution of 9.5 g.tartaric acid in hot isopropyl alcohol (65 ml.). The solution wasfiltered and allowed to cool. The precipitated crystals of the tartratewere removed by filtration, washed with a little cold isopropyl alcoholand dried. Yield 10.2 g, m.p. 158°-160° C., Found: C, 50.56% H, 5.67%;N, 7.90%. Calc. for C₁₅ H₂₀ N₂ O₆ S: C, 50.55% H, 5.65%; N, 7.86%.

EXAMPLE 33 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) andthioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50ml.), the solution saturated with dry hydrogen chloride gas and thenheated on a steam bath for 4 hours. The cooled reaction mixture waspoured onto water (200 ml.), washed with ethyl acetate (2× 200 ml.) andthe extracts discarded. The aqueous solution was adjusted to pH 10.0with 46% sodium hydroxide and extracted into methylene chloride (2× 200ml.). The combined extracts were dried (sodium sulphate), evaporated invacuo and the residual oil triturated with isopropanol and filtered.Recrystallisation from benzene gave the title compound as pale yellowneedles (1.3 g., 63%) m.p. 149°.

EXAMPLE 34 Methyl 3-methylcyclohepteno[b]pyridine-9-caboxylate.

3-Methylcyclohepteno[b]pyridine was prepared from cycloheptanone and3-amino-2-methyl-acrolein according to the method of Breitmaier (Tet.Lett 1970, 38, 3291) and in the manner described in the synthesis of5,6,7,8-tetrahydroquinoline (Example 11) and was isolated as acolourless oil b.p. 140°/14 mm.

A solution of 15% n-butyl lithium in hexane (16 ml. ca. 0.04 m) wasadded portionwise to a solution of 3-methylcyclohepteno[b]pyridine (5 g.0.03 m) in ether (50 ml.) under nitrogen and the mixture allowed tostand at room temperature for 30 minutes. The mixture was treated withCO₂ gas until the red colour was discharged and the solvent was removedin vacuo. The residue was dissolved in water (25 ml.) and extracted withether (3× 50 ml.). The aqueous solution was evaporated in vacuo and theresidue treated with methanol previously saturated with HCl gas (100ml.) and allowed to stand at room temperature for 12 hours. The solventwas removed and the residual oil was dissolved in water (50 ml.) andextracted with ether (3× 50 ml.). The aqueous solution was adjusted topH 9.0 with sodium carbonate and extracted into ether (3× 50 ml.). Thecombined extracts were dried, evaporated in vacuo to give the titlecompound as a pale yellow oil (0.8 g., 11%) GLC: R_(T) = 6.1/4 min.(F11, 10% SE30 , T= 150°). I.R. Spectrum: ν.sub. max^(film) 1740; 1460;1440, 1120-1200 (broad) cm.sup.⁻¹ .

EXAMPLE 35 Methyl 3-methylcyclopenteno[b]pyridine-7-carboxylate

3-Methylcyclopenteno[b]pyridine was prepared from cyclopentanone and3-amino-2-methylacrolein according to the method of Breitmaier (Tet.Lett. 1970, 38, 3291) and was isolated as a colourless oil b.p.100°-105°/15 mm.

A solution of 3-methylcyclopenteno[b]pyridine (10 g. 0.078 m.) in ether(150 ml.) was treated with a 15% solution of n-butyl lithium in hexane(30 ml. ca. 0.08 m) and the mixture treated with CO₂ gas. The lithiumsalt of 3-methylcyclopenteno[b]pyridine-8-carboxylic acid was isolatedand esterified with methanol previously saturated with HCL gas asdescribed for methyl3-methylcyclohepteno [b]pyridine-9-carboxylate(Example 34). The title compound was isolated as a pale yellow oil (1.1g., 10%) GLC R_(T) = 1.1/2min. (Pye 104, 3% SE30, T= 200° ). I.R.Spectrum ν_(max) ^(Film) 1738, 1460, 1422, 1160-1220 (broad) cm.sup.⁻¹.

EXAMPLE 36 Methyl3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline (17.5 g., 0.1 m) wasdissolved in dry ether (200 ml.) and treated with a solution of n-butyllithium in hexane (15% solution, 56 ml.) under nitrogen. The reactionmixture was allowed to stand at room temperature for 30 minutes and thentreated with CO₂ gas until the intense red colour was discharged. Thesolvent was removed and the residual oily solid dissolved in water (20ml.) then extracted with ether (3× 50 ml.). The ethereal extracts wereretained to recover unreacted starting material. The aqueous solutionwas evaporated to dryness, the residue treated with methanol previouslysaturated with dry HC1 (100 ml.) and the solution allowed to stand atroom temperature for 8 hours. The solvent was removed and the residualoil dissolved in water (50 ml.) and extracted with ether (3× 50 ml.) andthe extracts discarded. The aqueous solution was adjusted to pH 9.0 withsodium carbonate and extracted with ether (3× 50 ml.). The combinedextracts were dried and evaporated in vacuo to give the title compoundas a pale yellow oil (1.8 g., 10%) I.R. Spectrum ν.sub. max^(film) 1748,1570, 1460, 1160, 1030 cm.sup.⁻¹. GLC: R_(T) =3.1/2 min. (F11, 2% OV17,T= 150°).

The picrate of the title compound was formed by dissolving the free base(100 mg.) in ethanol (1 ml.) and adding a saturated solution of picricacid in ethanol (5 ml.) and allowing the picrate to crystallise. Thepicrate was removed by filtration, dissolved in the minimum volume ofethanol and precipitated by adding ether giving yellow needles m.p.95°-7°.

Analysis Found: C, 50.2; H, 4.7; N, 12.1% C₁₄ H₁₉ NO₂ picrate 3/4 H₂ ORequires: C, 50.5; H, 5.0; N, 11.8%

EXAMPLE 37 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

To a solution of 3-methyl,5,6,7,8-tetrahydroquinoline (10 g; 0.068 m.)in dry hexane (50 ml.) was added 50 ml. of a 15% solution of n-butyllithium in hexane (0.09 m.) dropwise with stirring under an atmosphereof nitrogen. The dark red solution was stirred for 15 minutes at roomtemperature and then treated with carbon disulphide (10 ml.) Theresulting pale yellow suspension was poured with water (100 ml.) and theaqueous solution was washed with ether (3× 100 ml.).

The aqueous solution of the lithium salt of3-methyl-5,6,7,8-tetrahydroquinoline-8-dithiocarboxylic acid was stirredvigorously and methyl iodide (40 ml.) added. The solution was stirred atroom temperature for 21/2 hours and extracted with ether (3× 75 ml.).The ether solution was dried over anhydrous magnesium sulphate andevaporated. Methyl 3-5,6,7,8-tetrahydroquinoline-8-dithiocarboxylate wasleft as a red oil.

The oil was dissolved in methanol previously saturated with ammonia (200ml.) and the solution allowed to stand for 16 hours. The solvent wasevaporated and the residue dissolved in ether (100 ml.). The etherealsolution was washed with water and the aqueous layer discarded. Thesolution was then extracted with 2N HC1 (50 ml.) and water (50 ml.). Thecombined extracts were washed with ether and the pH of the solutionadjusted to 9 with saturated sodium carbonate solution. The solution wasextracted with ether (3× 50 ml.) and the ethereal solution dried overanhydrous magnesium sulphate and evaporated to give the crude3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (2.5 g.) tlc. onSilica gel F254 in ethyl acetate: R_(f) =0.4 and in ethanol R_(f) =0.8identical with authentic material.

EXAMPLE 38 8-Cyano-5,6,7,8-tetrahydroquinoline

5,6,7,8-Tetrahydroquinoline-8-carboxamide (2 g.) was refluxed andstirred with P₂ S₅ (1.4 g.) in pyridine 25 ml. for three hours. Themixture was evaporated to dryness in vacuo and then dilute sodiumhydroxide was added to the residue followed by solid potassiumcarbonate. The product was extracted into chloroform and the chloroformextract washed with water and dried over MgSO₄. The dried extract wasevaporated to dryness and the residue purified using columnchromatography on silica gel with benzene/ethyl acetate (4:1) as eluent.The nitrile was dissolved in ethanol/ether and ethereal HCl added. Thesolution was evaporated to dryness giving the hydrochloride of the titlecompound as the quarter hydrate 800 mg. m.p. 185° C. dec. AnalysisFound: C, 60.8; H, 5.7; N, 14.0% C₁₀ H₁₀ N₂ HCl 1/4 H₂ O requiresC,60.5; H, 5.8; N, 14.10%

EXAMPLE 39 3-Methyl-5,6,7,8-Tetrahydroquinoline-8-carboxylic acid

Methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate(5 g.) was treated with10% NaOH (40 ml.) and heated under reflux for 11/2 hours. The cooledreaction mixture was extracted with ether and the aqueous layer wasacidified to pH7 with acetic acid filtered and evaporated to drynessunder reduced pressure. The residue was triturated with benzene. Thebenzene solution was filtered and evaporated under reduced pressure andthe residues were triturated with ether giving the sodium salt of thetitle compound as a white powder 1.8. g. Found C, 60.0; H, 5.6; N, 6.4%C₁₁ H₁₂ NO₂ Na.1/2 H₂ O requires C,59.6; H,5.8; N, 6.4% pKa 3.42, and6.72 were recorded.

A further 1.4 g. of the sodium salt was obtained by further extractionof the benzene insoluble material.

EXAMPLE 40 8-Cyano-3-Methyl-5,6,7,8-tetrahydroquinoline

3,Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (3.6 g.) in pyridine(54 ml.) was treated with P₂ S₅ (7.56 g.) and the mixture heated atreflux with stirring for 3 hours. The solvent was removed under reducedpressure and the residue cooled in ice-water then made basic with 10%NaOH. The basic solution was extracted with chloroform (3 times) and thecombined extracts extracted with 2N HC1 (twice). The combined acidextracts were basified with solid sodium carbonate and extracted intochloroform (3 times). The combined chloroform extracts were washed withbrine, dried (MgSO₄) and evaporated to give the title compound 1.7 g.This was converted to the hydrochloride by dissolving in ether andadding ethereal HCl. An oily residue was formed from which thesupernatant liquid was decanted. The residue was triturated twice withdry ether and the remaining solid recrystallised from isopropyl alcoholgiving the hydrochloride of the title compound m.p. 189° C. AnalysisFound: C, 63,08; H, 6.26; N, 13.34% C₁₁ H₁₂ N₂ HCl requires: C, 63.30;H, 6.28; N, 13.43%

EXAMPLE 41 2-Phenyl-4(4'-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

A hot solution of sodium hydroxide [(15 g. in water (15 ml.)] is addedto a solution of 1-phenyl-3-(4'-methoxyphenyl)prop-2-enone (10.7 g.0.045 mol.) and cyclohexanone (20 g. 0.2 mol.) in ethanol (150 ml.) at40° C. and the mixture stirred at room temperature for 12 hours. Thereaction mixture is diluted with water (200 ml.) and the resultant solidfiltered, dried and recrystallised from ethanol to give2-[β-benzoyl-α-(4'-methoxyphenylethyl)]cyclohexanone as colourlessneedles m.p. 148° C. (Found: C, 79.0, H. 7.4 C₂₂ H₂₄ O₃ requires: C,78.5; H, 7.2%).

A solution of 2-[β-benzoyl-α-(4'-methoxyphenylethyl)] cyclohexanone (7.60.021 mol.) in ethanol (25 ml.) is treated with hydroxylaminehydrochloride (3.42 g., 0.05 mol.) and the mixture heated at reflux withstirring for 2 hours. The cooled reaction mixture is diluted with water(50 ml.) and the pH adjusted to 1.0 with conc. HCl and extracted withether (2× 50 ml.) and the extracts discarded. The aqueous solution isadjusted to pH 9.0 with Na₂ CO₃ and extracted with ether (2× 50 ml.) andthe combined extracts washed with brine, dried (MgSO₄) and evaporated togive 2-phenyl-4-(4'-methoxyphenyl)-5,6,7,8-tetrahydroquinoline as acolourless oil (5.8 g.) which is converted into methyl2-phenyl-4(4'-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-8-carboxylatefollowing the method described in Example 19. The ester is convertedinto2-phenyl-4-(4'-methoxyphenyl-5,6,7,8-tetrahydroquinoline-8-carboxamidefollowing the method described in Example 22. The amide is convertedinto the title compound following the method described in Example 23.

EXAMPLE 42 3,8-Dimethyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

3,8-dimethyl-8-cyano-5,6,7,8-tetrahydroquinoline is treated with H₂ S inpyridine in the presence of triethylamine following the generalprocedure of Example 5 and the title compound is isolated andrecrystallised from benzene as the quarter hydrate, colourless meedlesm.p. 164° C. This was converted to the hydrochloride by treatment inisopropanol with a solution of dry HCl gas in ether. The title compoundhydrochloride crystallised as colourless needles m.p. 277° C.

EXAMPLE 43 4-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

Following the general procedures of Examples 19, 22 and 23,4-methyl-5,6,7,8-tetrahydroquinoline is converted to the title compound,which is obtained as the hydrochloride, colourless needles m.p. 213° C.

EXAMPLE 44 3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline-thiocarboxamide

Methyl 3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline-8-carboxylateobtained as described in Example 36 is converted to the 8-carboxamidefollowing the general procedure of Example 22. The product is treatedwith phosphorus pentasulphide and H₂ S in pyridine following the generalprocedure of Example 23 to give the title compound which is converted tothe hydrochloride. The hydrochloride of the title compound isrecrystallised from isopropanol as a 11/4 hydrate m.p. 162° C.

EXAMPLE 451,2,3,5,6,7-Hexahydro-dicyclopenta[b,e]pyridine-3-thiocarboxamidehydrochloride

A mixture of 2-(dimethylaminomethyl)cyclopentanone (87 g.) andcyclopentanone (210 g.) was heated at reflux for 12 hours. The excesscyclopentanone was removed by distillation and the residue was dissolvedin ethanol (300 ml.) and treated with hydroxylamine hydrochloride (100g.) and the mixture heated at reflux for 11/2 hours. The cooled reactionmixture was dissolved in water (1 liter), washed with ether (3× 200 ml.)and the aqueous phase adjusted to pH 10.0 with sodium carbonate andextracted with ether (3× 200 ml.) The combined extracts were dried(MgSO₄) and the solvent removed to give a residual oil which wasdistilled at 0.2 mm to give 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine as a colourless oil (50 g.) b.p.100° C. The pyridine isconverted to the methyl 3-carboxylate following the method described inExample 19 and the carboxylate converted to1,2,3,5,6,7-hexahydro-dicyclopenta[b,e]pyridine-3-carboxamide, by thegeneral method described in Example 17. The carboxamide is isolated ascolourless needles from methanol m.p. 188° C. (Found: C,71.1: H,7.2; N,14.3. C₁₂ H₁₄ N₂ O requires: C, 71.3; H,7.0; N,13.9%).

The carboxamide (1.9 g.) is converted to the thioamide by the methoddescribed in Example 23 and isolated as pale yellow solid which isconverted to the hydrochloride by treating a solution of the base (600mg.) in methanol (5 ml.) with excess ethereal hydrogen chloride. Theresultant solid is recrystallised from methanol-ether to give the titlecompound as colourless needles m.p. 299° C. (Found: C,56.4; H.6.1;N,10.8. C₁₂ H₁₄ N₂ S. HC1 requires: C,56.6; H, 5.9; N,11.0%).

EXAMPLE 46 3-Methyl-cyclopenteno[b]pyridine-7-thiocarboxamide

The methyl carboxylate product of Example 35 is treated with methanolsaturated with ammonia gas as described in Example 17 to obtain3-methyl-cyclopenteno[b] pyridine-7-carboxamide m.p. 159° C. This isconverted to the title compound hydrochloride (m.p. 198°-202° C.) by thegeneral method of Example 23.

EXAMPLE 475,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-thiocarboxamide

2-(oxo-cyclopentyl)methyl cyclohexanone is prepared from2-(dimethylaminomethyl)-cyclohexanone and cyclopentanone according tothe method described in Ann.Chim.,1963, 53 (6), 819 and is isolated as acolourless oil in 80% yield b.p. 92°/0.05 mm.5,6,7,8-Tetrahydro-2,3-dihydro-1H-cyclopenta [b]quinoline is preparedfrom 2-(2-oxocylopentyl)methylcyclohexanone according to the methoddescribed in Ann.Chim., 1963, 53,(6), 819 and is isolated in 65% yieldas a colourless oil b.p. 80°/0.05 mm. The hydrochloride is prepared forcharacterisation by treating an ethereal solution of the base withethereal HC1 and is isolated as the hemi-hydrate as colourless needlesfrom ethanol-ester m.p. 104° C(Found: C65.7; H,7.8; N,6.6 C₁₂ H₁₆N.HC1.1/2H₂ O requires: C,65.8; H,7.8; N,6.4%.5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline is convertedto methyl5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]quinoline-5-carboxylatefollowing the method described in Example 19 and this is converted to5,6,7,8-tetrahydro-2,3-dihydro-1H-cyclopenta[b]-quinoline-5-carboxamidefollowing the method described in Example 22. The amide is converted tothe title compound, following the procedure of Example 23, and isrecrystallised from isopropanol, dissolved in ether and treated with anexcess of ethereal HC1. The resultant solid is recrystallised fromethanol-ether to give the hydrochloride of the title compound as themonohydrate m.p. 118° C. )Found: C,54.6; H,6.3; N,10.0 C₁₃ H₁₆ N₂ S.HClH₂ O requires: C,54.4; H,6.6; N,9.8%).

EXAMPLE 48

Following the procedure of Example 28 but substituting the followingstarting material for the ester and amine respectively the followingproduct is obtained:

    ______________________________________                                        ester        amine     thioamide                                              ______________________________________                                        methyl-3-methyl-                                                                           ethylamine                                                                              3-methyl-cyclopenteno-                                 cyclopenteno-[b]-      [b]pyridine-7-(N-ethyl)-                               pyridine-7-carboxy-    thiocarboxamide                                        late                                                                          ______________________________________                                    

EXAMPLE 49

Following the procedure of Example 46 but substituting the followingstarting materials the following end products are obtained:

    ______________________________________                                        starting material end product                                                 ______________________________________                                        methyl-2-methyl-cyclopenteno-                                                                   2-methyl-cyclopenteno-                                      [b]-pyridine-7-carboxylate                                                                      [b]-pyridine-7-thio-                                                          carboxamide.                                                methyl-4-methyl-cyclopenteno-                                                                   4-methyl-cyclopenteno-                                      [b]pyridine-7-carboxylate                                                                       [b]-pyridine-7-thio-                                                          carboxamide.                                                methyl-5-methyl-cyclopenteno-                                                                   5-methyl-cyclopenteno-                                      [b]-pyridine-7-carboxylate                                                                      [b]pyridine-7-thio-                                                           carboxamide                                                 methyl-3-phenyl-cyclopenteno-                                                                   3-phenyl-cyclopenteno-                                      [b] -pyridine-carboxylate                                                                       [b]-pyridine-7-thio-                                                          carboxamide                                                 methyl-4-phenethyl-cyclo                                                                        4-phenethyl-cyclopenteno-                                   penteno[b]-pyridine-7-                                                                          [b]-pyridine-7-thio-                                        carboxylate       carboxamide                                                 ______________________________________                                    

EXAMPLE 50

Following the procedure of the indicated Example but substitutinganother alcohol for methyl alcohol the following ester is prepared:

    ______________________________________                                        Example  Alcohol     Ester obtained                                           ______________________________________                                        35       t-butanol   t-butyl-3-methyl-cyclopenteno-                                                [b]pyridine-7-carboxylate                                ______________________________________                                    

We claim:
 1. A compound of formula I ##STR12## and acid addition saltsthereof with pharmaceutically acceptable acids, wherein R¹, R² and R⁶are the same or different and are selected from hydrogen,trifluoromethyl, alkyl containing from 1 to 6 carbon atoms, phenylalkylwherein the alkyl group has 1-6 carbon atoms, or phenyl groups or R¹ andR² taken together represent a polymethylene chain of 3 to 5 carbonatoms, R⁷ represents hydrogen or 1 or 2 groups selected from alkyl of 1to 6 carbon atoms (which may be substituted by alkoxy of 1 to 6 carbonatoms or trifluoromethyl), phenylalkyl wherein the alkyl group has 1 to6 carbon atoms and phenyl groups, X is CONHR³ or CO₂ R⁵ wherein R³ ishydrogen or alkyl of 1 to 6 carbon atoms and R⁵ is hydrogen, alkyl of1-6 carbon atoms or phenylalkyl wherein the alkyl portion has 1-6 carbonatoms and any of the phenyl or the phenyl portion of any phenylalkylgroups R¹, R², R⁵, R⁶ and R⁷ may be substituted by alkyl of 1 to 6carbon atoms, lower alkoxy of 1 to 6 carbon atoms, halogen, nitro ortrifluoromethyl and metal salts of compounds wherein R⁵ is hydrogen withthe provisos that (1) when R¹ and R² or R² and R⁶ are both alkyl theyare selected from normal and secondary alkyl groups and (2) when twoalkyl R⁷ groups are present on the same carbon atom then they are bothn-alkyl groups and when two R⁷ alkyl groups are present on adjacentcarbon atoms they are selected from normal and secondary alkyl groups.2. A compound as claimed in claim 1, or an acid addition salt thereofwith a pharmaceutically acceptable acid wherein R¹, R², R⁶ and R⁷ arethe same or different and are selected from hydrogen and lower alkyl of1 to 4 carbon atoms, and R³ is hydrogen or methyl.
 3. A compound asclaimed in claim 1 wherein R¹, R², and R⁶ are selected from hydrogen andmethyl.
 4. A compound as claimed in claim 1 which has the formula##STR13## and pharmaceutically acceptable acid addition salts thereofwherein R¹ is hydrogen or alkyl of 1-6 carbon atoms, R⁷ is hydrogen oralkyl of 1-6 carbon atoms and X is CONHR³ or CO₂ R⁵ wherein R³ ishydrogen or alkyl of 1-6 carbon atoms and R⁵ is hydrogen or alkyl of 1-6carbon atoms and alkali metal salts of compounds where X is CO₂ R⁵wherein R⁵ is hydrogen.
 5. A compound as claimed in claim 1 which ismethyl 3-methylcyclopenteno[b]pyridine-7 -carboxylate.
 6. A compound asclaimed in claim 1, which is1,2,3,5,6,7-hexahydro-dicyclo-penta[b,e]pyridine-3-carboxamide.
 7. Acompound as claimed in claim 1, which is3-methylcyclopenteno[b]pyridine-7-carboxamide.